Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump

Olga V. Fedorova, Vladimir A. Kashkin, Irina O. Zakharova, Edward Lakatta, Alexei Y. Bagrov

Research output: Contribution to journalArticle

Abstract

Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P<0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.

Original languageEnglish (US)
Pages (from-to)1817-1826
Number of pages10
JournalJournal of Hypertension
Volume30
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

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Sodium-Potassium-Exchanging ATPase
Atrial Natriuretic Factor
Blood Vessels
Salts
Kidney
Cyclic GMP-Dependent Protein Kinases
Guanylate Kinases
Natriuresis
Aorta
Down-Regulation
marinobufagenin
Type 5 Cyclic Nucleotide Phosphodiesterases
sodium-translocating ATPase
Cyclic GMP
Vasoconstriction
Sprague Dawley Rats

Keywords

  • aging
  • cyclic guanosine monophosphate
  • dietary sodium
  • hypertension
  • marinobufagenin
  • Na/K-ATPase
  • natriuretic peptides
  • protein kinase G
  • salt sensitivity

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump. / Fedorova, Olga V.; Kashkin, Vladimir A.; Zakharova, Irina O.; Lakatta, Edward; Bagrov, Alexei Y.

In: Journal of Hypertension, Vol. 30, No. 9, 09.2012, p. 1817-1826.

Research output: Contribution to journalArticle

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abstract = "Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20{\%}, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7{\%}, P<0.01), 30{\%} less natriuresis, and less inhibition of renal NKA (25 vs. 42{\%}, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.",
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T1 - Age-associated increase in salt sensitivity is accompanied by a shift in the atrial natriuretic peptide modulation of the effect of marinobufagenin on renal and vascular sodium pump

AU - Fedorova, Olga V.

AU - Kashkin, Vladimir A.

AU - Zakharova, Irina O.

AU - Lakatta, Edward

AU - Bagrov, Alexei Y.

PY - 2012/9

Y1 - 2012/9

N2 - Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P<0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.

AB - Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG. Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro. Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10mmHg, P<0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P<0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P<0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition. Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.

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KW - dietary sodium

KW - hypertension

KW - marinobufagenin

KW - Na/K-ATPase

KW - natriuretic peptides

KW - protein kinase G

KW - salt sensitivity

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